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Insulin receptors are distributed in the whole brain, including different parts of the reward circuit that modulate dopamine as the primary neurotransmitter implicated in addiction. The goal of the current study was to illuminate the role of insulin in the extinction period and reinstatement of morphine-induced conditioned place preference (CPP) in the naïve and diabetic rats. One hundred and twelve male rats were randomly divided into two naïve and diabetic groups. Diabetes was induced by one dose administration of streptozotocin (STZ; 60 mg/kg; IP) ten days before the conditioning procedure. To evaluate the insulin's role in the duration of extinction period of morphine-CPP, naïve and diabetic rats received insulin (10 U/kg; IP) before each morphine injection (5 mg/kg; sc) during the 3-day conditioning phase. All rats that passed the conditioning phase and then underwent the extinction period. Morphine priming-induced reinstatement was determined in both naïve and diabetic rats by injection of different ineffective doses of morphine (0.5 and 1 mg/kg; sc) in extinguished rats. In the following experiments, three groups of diabetic rats received insulin during the conditioning, expression, or reinstatement phase to illustrate insulin's effect on the morphine-induced reinstatement and the duration of the extinction period (insulin was only treated during the acquisition phase). The results showed that the extinction period and reinstatement of morphine were potentiated in the STZ-induced diabetic rats. The obtained findings also revealed that insulin replacement shortened the extinction period of morphine-induced CPP in STZ-diabetic rats. However, insulin replacements in conditioning, expression, and reinstatement phases did not affect morphine priming-induced reinstatement in diabetic animals.

Diabetes mellitus is a chronic illness that has been associated with the decrease of insulin in type I diabetes. Insulin has an impact not only on the direct control of food intake and plasma glucose levels, but also on brain pathways associated with reward. It affects brain reward pathways through regulation of the dopamine (DA) transporter (DAT). Moreover, it has been found to affect the ability of drugs that target the DA system. In the present study, the effects of streptozotocin (STZ)-induced diabetes on the acquisition (development) and maintenance of morphine-induced conditioned place preference (CPP) were investigated in rats. Forty adult male Albino Wistar rats were used in these experiments. For induction of diabetes, STZ was administered at a dose of 60 mg/kg. After seven days, the CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The results showed that diabetes significantly increased the magnitude of conditioning scores, acquisition of morphine-induced CPP in compared to naive animals (P0.05). Moreover, in the diabetic group, there were significant differences among conditioning scores in the post-conditioning phase and the last four days (7th-10th), but these differences elongated up to 10 days after the CPP protocol while the extinction period was eight days in the naive group. Our findings indicated that the magnitude and maintenance of morphine rewarding properties have been changed in STZ-induced diabetic animals. It seems that a level of insulin and their receptors are involved in the development and maintenance of morphine-induced CPP in the rats.